The discovery of fingolimod (FTY720/Gilenya; Novartis), an orally active immunomodulatory drug, has opened up new approaches to the treatment of multiple sclerosis, the most common inflammatory disorder of the central nervous system. Elucidation of the effects of fingolimod--mediated by the modulation of sphingosine 1-phosphate (S1P) receptors--has indicated that its therapeutic activity could be due to regulation of the migration of selected lymphocyte subsets into the central nervous system and direct effects on neural cells, particularly astrocytes. An improved understanding of the biology of S1P receptors has also been gained. This article describes the discovery and development of fingolimod, which was approved by the US Food and Drug Administration in September 2010 as a first-line treatment for relapsing forms of multiple sclerosis, thereby becoming the first oral disease-modifying therapy to be approved for multiple sclerosis in the United States.

A novel series of alkoxyimino derivatives as S1P 1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure− activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid (32, BAF312, Siponimod), which has recently completed phase 2 clinical trials in patients with relapsing−remitting multiple sclerosis.

Objective: To report outcomes of pregnancies that occurred during the fingolimod clinical development program.Methods: Pregnancy outcomes from phase II, phase III, and phase IV clinical studies (with optional extensions) were reported by clinical trial investigators. Fingolimod exposure in utero was defined as fingolimod treatment at the time of conception or in the 6 weeks before conception.Results: As of October 31, 2011, 89 pregnancies were reported in completed or ongoing clinical studies, with 74 in fingolimod treatment arms. Of 66 pregnancies with in utero exposure to fingolimod, there were 28 live births, 9 spontaneous abortions, 24 elective abortions, 4 ongoing pregnancies, and 1 pregnancy with an unknown outcome (patient lost to follow-up). Two infants were born with malformations: 1 with congenital unilateral posteromedial bowing of the tibia and 1 with acrania. Elective abortions were performed for 1 case each of tetralogy of Fallot, spontaneous intrauterine death, and failure of fetal development. There were 5 cases (7.6%; 95% confidence interval 3%-17%) of abnormal fetal development in the 66 pregnancies that had in utero exposure to fingolimod. In all 5 cases, fetal exposure to the drug took place in the first trimester of pregnancy. Conclusions:The number of patients becoming pregnant during fingolimod therapy remains small and does not permit firm conclusions to be drawn about fetal safety of fingolimod in humans. Given the known risks of teratogenicity in animals and the present data, women of childbearing potential should use effective contraception during fingolimod therapy and for 2 months after discontinuation. Neurology ® 2014;82:674-680 GLOSSARY CI 5 confidence interval; MS 5 multiple sclerosis.Multiple sclerosis (MS) is predominant among women of reproductive age, in whom approximately 50% of all pregnancies are unplanned.1 Fingolimod (FTY720; Gilenya, Novartis Pharma AG, Basel, Switzerland) is a sphingosine 1-phosphate receptor modulator that has been approved as a once-daily oral therapy for relapsing MS. Two phase II studies, 3 large-scale phase III studies, and their ongoing extension studies have indicated that fingolimod has a manageable safety profile and is generally well tolerated at the approved dose of 0.5 mg. [2][3][4][5][6] As preclinical studies indicate a risk of fetal toxicity, 7 fingolimod clinical study protocols require a negative pregnancy test at enrollment and that women of childbearing potential use reliable contraception throughout the studies. We report the outcomes of pregnancies that occurred in the fingolimod clinical development program despite these measures.METHODS Standard protocol approvals, registrations, and patient consents. Pregnancy outcomes are reported from 9 clinical studies in patients with relapsing MS: the phase III FREEDOMS study 3